Article | Published:

Functional RNAs exhibit tolerance for non-heritable 2′–5′ versus 3′–5′ backbone heterogeneity

Nature Chemistry volume 5, pages 390394 (2013) | Download Citation

Abstract

A plausible process for non-enzymatic RNA replication would greatly simplify models of the transition from prebiotic chemistry to simple biology. However, all known conditions for the chemical copying of an RNA template result in the synthesis of a complementary strand that contains a mixture of 2′–5′ and 3′–5′ linkages, rather than the selective synthesis of only 3′–5′ linkages as found in contemporary RNA. Here we show that such backbone heterogeneity is compatible with RNA folding into defined three-dimensional structures that retain molecular recognition and catalytic properties and, therefore, would not prevent the evolution of functional RNAs such as ribozymes. Moreover, the same backbone heterogeneity lowers the melting temperature of RNA duplexes that would otherwise be too stable for thermal strand separation. By allowing copied strands to dissociate, this heterogeneity may have been one of the essential features that allowed RNA to emerge as the first biopolymer.

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Acknowledgements

J.W.S. is an Investigator of the Howard Hughes Medical Institute (HHMI). A.E.E. is supported by an appointment to the NASA Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA. M.W.P. was an HHMI Research Associate. This work was supported in part through NSF Grant CHE-0809413 to J.W.S. We thank J. Craig Blain for oligonucleotide mass spectrometry, K. Adamala for advice with RNA melting experiments and N. Prywes for helpful discussions and assistance with figure preparation.

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Author notes

    • Matthew W. Powner

    Present address: Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H 0AJ, UK

Affiliations

  1. Howard Hughes Medical Institute, Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Aaron E. Engelhart
    • , Matthew W. Powner
    •  & Jack W. Szostak

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Contributions

All authors contributed to the design of the experiments and to writing the paper. Experiments were conducted by A.E.E. and M.W.P.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jack W. Szostak.

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DOI

https://doi.org/10.1038/nchem.1623

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